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Nghiên cứu đặc điểm lâm sàng, nồng độ CRP, TNF α huyết thanh và biển đổi một số chỉ số hình thái, chức năng tim ở bệnh nhân viêm khớp dạng thấp tt tiếng anh

MINISTRY OF EDUCATION
MINISTRY OF DEFENCE
AND TRAINING
VIETNAM MILITARY MEDICAL UNIVERSITY

HOANG TRUNG DUNG

STUDY ON CLINICAL CHARACTERISTICS,
PLASMA CRP LEVEL, SERUM TNF-α AND AlTERATIONS
OF SOME CARDIAC MORPHOLOIC AND FUNCTIONAL
PARAMETERS IN RHEUMATOID ARTHRITIS PATIENTS

Specialty

: INTERNAL MEDICINE

Code

: 9 72 01 07

THE SUMMARY OF THE MEDICAL DOTORAL THESIS


HANOI - 2019


THIS DOCTORAL THESIS WAS COMPLETED
AT VIETNAM MILITARY MEDICAL UNIVERSITY

Scientific Instructors:
1. A/PROF. Ph.D. Doan Van De
2. Ph.D. Vien Van Doan

1st Contradictor: A/PROF. PhD. Le Thu Ha
2nd Contradictor: A/PROF. PhD. Phan Thi Thu Anh
3rd Contradictor: A/PROF. PhD. Nguyen Thi Phi Nga

The doctoral thesis will be reported to The Grading and
Examinations Committee hold at Vietnam Military Medical
University at ….2018

Searching for the dissertation at:
-

National Library

-

Vietname Military Medical University’s library


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INTRODUCTION
Rheumatoid arthritis (RA) is a chronic autoimmune arthritis. In
addition to joint destruction, it can damage the heart, lungs… This is
a severe prognostic factor that can lead to death.
C Reactive Protein (CRP) is a protein produced in inflammatory
response. CRP level is also related to cardiovascular events. The role
of TNF-α (Tumor Necrosis Factor-alpha) in the pathogenesis of RA
has been increasingly investigated. TNF-α not only plays a role in
evaluating the therapeutic response but is also a cardiovascular risk
factor.
The leading cause of death in patients with RA is cardiovascular
damage. Cardiovascular manifestations of RA are often discreet. If not
detected early and treated promptly, heart damage will affect the quality
of life and the risk of death of patients with RA. One of the methods of
comprehensive evaluation of cardiac dysfunction is Doppler
ultrasonography.
Therefore, the thesis "Study on clinical characteristics, plasma
CRP level, serum TNF-α and alterations of some cardiac
morphologic and functional parameters in rheumatoid arthritis
patients" was conducted with two objectives:
1. To describe the clinical, subclinical features, plasma CRP
level, serum TNF-α level and some cardiac morphologic and
functional parameters in patients with rheumatoid arthritis.
2. To understand the relationship between clinical and subclinical
characteristics, plasma CRP level, serum TNF-α level, level of
disease activity with some cardiac morphologic and functional
parameters in rheumatoid arthritis patients.


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* The scientific significance
This study investigated changes in plasma CRP level, serum TNF-α
level and some cardiac morphologic and functional indexes of RA patients
compared with that of control group and the association between some
cardiac morphologic and functional parameters with clinical and
subclinical characteristics.
* The practical significance
This research shows that plasma CRP level and serum TNF-α
level of RA patients were higher than that of the control group.
35.2% of RA patients had left ventricular (LV) diastolic dysfunction
(DD). The research reveals the relationship between some cardiac
morphologic and functional parameters with clinical and clinical
characteristics in patients with RA.
* New contributions of this doctoral thesis
- This is the first scientific study in Vietnam researching Tissue
Doppler Imaging (Doppler myocardial imaging) in RA patients.
- The study shows that serum TNF-α level of rheumatoid arthritis
patients was higher than that of patients in the control group and
there is no correlation between it and clinical and subclinical features.
- Even though patients had no clinical symptoms the results of the
study shows that more than 35.2% of RA patients had left ventricular
diastolic dysfunction and there is a strong correlation between Em at
septal mitral annulus and disease duration and age. Therefore,
screening left ventricular diastolic function should be performed on
patients with RA with a duration of more than 5 years and patients
aged over 60 years old.
* The doctoral thesis arrangement: This thesis contains 132
pages (without references and appendixes): Introduction: 02 pages,
Chapter 1 Overview: 34 pages, Chapter 2 Subjects and methods: 25
pages, Chapter 3 Results: 33 pages, Chapter 4 Discussion: 34 pages,
Conclusion: 02 pages, Recommendations: 01 page. It includes 35
tables, 18 graphs, 10 figures, and 135 references (17 Vietnamese
references and 118 English references).


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CHAPTER 1: OVERVIEW
1.1. Overview of rheumatoid arthritis
1.1.1. History of research
RA is a systemic disease characterized by chronic inflammation of
the synovial membrane. The disease has been known since 1940 by
Waaler.
1.1.2. Clinical symptoms
The common clinical symptoms include morning stiffness,
symmetrical polyarticular joint swelling and pain in the hands, feet,
wrists, ankles, elbows, knees, shoulders, groin. RA can possibly
lead to joint deformities of hands and feet in the later stages of
the disease.
Common extra-articular manifestations: cardiac disease,
pulmonary involvement, chronic anemia, subcutaneous nodules.
1.1.3. Subclinical symptoms
Elevated CRP level, elevated ESR, RF tests, anti-CCP, hand Xray, joint ultrasound, joint MRI.
1.1.4. Diagnosis of rheumatoid arthritis
Diagnosis of RA is based on the ACR 1987 criteria. Recently, the
ACR / EULAR 2010 criteria has been used to diagnose early RA.
1.1.5. Evaluate the level of disease activity
Evaluating level of disease activity plays an important role in the
prognosis of RA and is the determinant factor (decision-making) in
choosing appropriate treatment options.
In addition to the criteria: the number of painful and swollen
joints, duration of morning stiffness, CRP concentration, erythrocyte
sedimentation rate (ESR), ACR and EULAR recommend using
DAS28 CRP, DAS28 ESR, CDAI, SDAI.
1.1.6. Treatment of rheumatoid arthritis
Internal medicine includes non-drug treatments and medication.
Medications include: anti-inflammatory medications - NSAIDs and
glucocorticoids, analgesics and DMARDs. There are two classes of
DMARDs: non-bioactive DMARDs and biological DMARDs.
1.2. Mechanism of pathogenesis and role of CRP, serum TNF-α
1.2.1. New view of the pathogenesis of rheumatoid arthritis
RA is a chronic inflammatory autoimmune disease in which immune
tolerance is broken causing to abnormal immune responses to antigens.
Genetic factors along with the environmental factors may activate the
development of RA, activate T cell in synovial membrane via T-CD4 +.


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Chronic inflammation of synovial membrane and destruction of
articular cartilage are caused under the regulation of cells: T-CD4 +,
Th1 and Th17, B lymphocytes, proinflammatory cytokines: TNF-α,
IL-1, IL-6 ..., as the consequence, pannus formation and articular
cartilages degradation lead to joint fibrosis, adhesion and deformity.
1.2.2. C Reactive Protein
CRP is a protein synthesized during inflammation. CRP level are
associated with a high risk of cardiovascular events in patients with RA.
Cardiovascular disease is a chronic inflammatory disease with the
increase in level of inflammatory markers, especially CRP and TNF-α.
CRP affects the pathogenesis of atherosclerosis and endothelial
dysfunction. CRP activates arterial endothelium to cause atherosclerosis.
1.2.3. Tumor necrosis factor alpha
TNF-α is a proinflammatory cytokine that plays an important role
in the pathogenesis of RA. TNF-α not only stimulates the cells
secreting it but also stimulates the production of other inflammatory
cytokines such as IL-1, IL-6, IL-8. TNF-α regulates the balance
between bone formation and bone turnover, causes arthritis and
cartilage destruction.
TNF-α is involved in the pathogenesis of many cardiovascular
diseases including atherosclerosis, myocardial infarction, cardiac
failure, and myocarditis.
1.3. Cardiac involvement and the role of Tissue Doppler Imaging
(TDI) in cardiac morphologic and functional evaluation
1.3.1. Cardiac involvement in rheumatoid arthritis
- Cause: inflammation induces CRP level, erythrocyte
sedimentation rate, TNF-α, RF. Due to the effects of medications:
Glucocorticoid, NSAIDs, Methotrexatr, anti-TNF-α drugs.
- Cardiac involvement includes: pericarditis, cardiomyopathy,
myocardial ischemia, amyloid cardiomyopathy, cardiac dysrhythmia,
valvular heart disease.
- Mechanism of cardiac damage: T cells, T-CD4 +, T ‘CD28null’
1.3.2. The role of Tissue Doppler Imaging in cardiac morphologic
and functional evaluation
- Left Ventricular Morphology Assessment on T mode:
Measurements for Dd, Ds, IVSTd, IVSTs, LVPWD, LVPWs, LVM,
EVD, ESV, FS, EF, CO.
- Doppler ultrasound: Measurements of E wave, A wave, E / A
ratio, DT, IVCT, IVRT, ET.
- Left ventricular (LV) Tei index = (IVCT + IVRT) / ET


5
- Tissue Doppler imagining at the interventricular septum and
lateral mitral annulus: Measurements of Sm wave, Em wave, Am
wave, E / Em ratio, Em / Am ratio.
1.4. Domestic and foreign studies
1.4.1. Overseas studies
According to Shrivastava A.K. et al. (2015) and Hanan M. et al.
(2015): serum CRP, TNF-α levels were higher than that of the control
group.
Wislowska M. et al. (2008), Sitia S. et al. (2012), Fatma E. et al.
(2015): left ventricular morphologic indexes of RA patients and
controls were the same. There were changes in cardiac functions,
especially left ventricular diastolic function in patients with RA
compared with the control group. Studies have shown that some
cardiac function indexes correlate with age, duration of disease,
plasma CRP level, serum TNF-α level in patients with RA.
1.4.2. Studies in Vietnam
Up to now, there have been no published studies on the role of TNFα and some morphological and cardiac indexes in Tissue Doppler
Imaging and the association between some cardiac morphologic and
functional indexes and clinical and subclinical characteristics.

CHAPTER 2: SUBJECTS AND METHODS
2.1. Subjects
The study included 122 active RA patients and 51 healthy controls.
2.1.1. Study group
Inclusion criteria:
- Diagnosed with RA based on American College of Rheumatology ACR 1987 criteria.
- No clinical manifestations of cardiovascular disease.
- Consent to participate in the study.
Exclusion criteria:
- Patients with cardiovascular disease such as heart valve disease,
congenital heart disease, valve regurgitation grade 2-4, cardiac
arrhythmias.
- Patients with pneumonia, pulmonary tuberculosis, pleural effusion,
infectious arthritis, diabetes mellitus, hypertension, scleroderma,
systemic lupus erythematosus.


6
- Patients did not consent to participate in the study.
2.1.1. Control group
Inclusion criteria:
- People at the same age and gender
- No history of arthritis, cardiovascular disease and medical conditions.
- Consent to participate in the study.
Exclusion criteria:
- Patients with definitive diagnosis or suspected cardiovascular
disease: based on clinical findings and electrocardiogram: chest pain
on examination, history of angina pectoris, history of diagnosed
myocardial infarction, heart failure, cardiac arrhythmias. Based on
echocardiography: mitral stenosis and/or aortic valve stenosis and/or
tricuspid stenosis at any grade, mitral regurgitation and/or aortic valve
regurgitation and/or tricuspid regurgitation grade 2 or more, left
ventricular
systolic
dysfunction,
regional
wall
motion
dysfunction/abnormalities, interventricular septal thickness and/or left
ventricle posterior wall thickness, left ventricular dilatation.
- Patients did not consent to participate in the study.
2.1.3. Time and place
This study was conducted from October 2014 and April 2018 at the
Department of Rheumatology, Bachmai Hospital.
2.2. Research Methods
2.2.1. Study Design: Prospective, descriptive cross-sectional study.
2.2.2. Sampling method:
2
. p.q
Sampling Size Formula:
n = Z 1− a / 22
According to Liang K.P. et al. (2010). 31% of patients
d with
rheumatoid arthritis had left ventricular diastolic dysfunction. Select
p = 0.31 to form a sample size of at least 82 patients. This study was
conducted on 122 patients (n = 122).
2.2.3. Steps to conduct research
Research subjects were examined clinically, the following
investigations were done: laboratory tests, plasma CRP level, serum
TNF-α level, Chest X-ray, Electrocardiography, Tissue Doppler
Imaging.
- Patients with rheumatoid arthritis were examined clinically and
assessed the level of disease activity: duration of disease, duration of
morning stiffness, the number swollen joints, the number of pain joints,
VAS scores, CDAI, SDAI, DAS28 CRP, DAS28 ESR.
- Complete Blood count (CBC), erythrocyte sedimentation
rate (ESR) 1 hr, 2 hrs, rheumatoid factor (RF).


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- CRP level measurement by measuring turbidity on AU 5800
with Beckman Coulter test.
- TNF-α concentration measurement: using CLIA on the Immulite
1000 System from Siemens.
- Posterior-anterior chest X-ray
- Electrocardiography
- Tissue Doppler Imaging
- Morphological assessment on echocardiography T mode:
measurement of Dd, Ds, IVSTd, IVSTs, LVPWD, LVP, LVM, EVD,
ESV, FS, EF, CO.
- Doppler echocardiography: Measurements of E wave, A wave,
E/A ratio, DT, IVCT, IVRT, ET.
- Left ventricular index
- Doppler ultrasound of at interventricular septum and lateral
mitral annulus: Measurements of Sm, Em, Am, E/Em, Em/Am.
2.2.4. Criteria used in research
- Assessment of BMI according to the World Health Organization.
- Diagnosis of RA according to ACR 1987
- Assessment of clinical symptoms: duration of disease, duration
of morning stiffness, the number of tender joins, the number of
swollen joints, VAS score.
- Diagnosis of level of disease activity: DAS28 CRP
- Diagnosis of anemia based on Hb concentration according to the
World Health Organization
- Diagnosis of left ventricular systolic dysfunction: EF%
- Diagnosis of left ventricular diastolic dysfunction according to
the American Society of Echocardiography 2009
2.2.5. Research parameters
- Clinical parameters: age, sex, BMI, BSA, systolic blood
pressure, diastolic blood pressure.
- Duration of disease: divided into 3 groups: ≤ 1 year; 1 to 5 years;
≥ 5 years.
- Duration of morning stiffness: < 45 minutes; 45 to 60 minutes; >
60 minutes.
- The number of tender joints, the number of swollen joints
- VAS scores (3 levels): 10 - 40; 50 - 60; 70 - 100
- CDAI, SDAI
- DAS28 CRP: DAS28 CRP < 2.6; 2.6 ≤ DAS28 CRP ≤ 3.2; 3.2 ≤
DAS28 CRP ≤ 5.1; DAS28 CRP > 5.1
2.2.5.2. Sub-clinical parameters


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- Complete blood count, erythrocyte sedimentation rate 1hr, 2 hrs.
- Diagnosis of anemia: Hb < 130 (g/L) in men and Hb < 120 (g/L)
in women. Classification: Hb > 110 (g/L): mild anemia; Hb: 80 - 109
(g/L): moderate anemia; Hb < 80 (g/L): severe anemia.
- Immunological tests: RF concentration (IU / mL). Evaluation:
RF < 14 IU/mL: negative; 14 IU/mL ≤ RF ≤ 42 IU/mL: low positive;
RF > 42 IU/mL: high positive.
2.2.5.3. Assessment of inflammation level
Measure plasma CRP level (mg/dL)
Measure serum TNF-α level (pg/mL)
2.2.5.4. Tissue Doppler Imaging
- Parameters for cardiac morphology:
+ Left ventricular end-diastolic diameter (Dd - mm)
+ Left ventricular end-diastolic diameter (Ds - mm)
+ Interventricular septal end diastole thickness (IVSd - mm)
+ Interventricular septal end systole thickness (IVSs - mm)
+ Left ventricular posterior wall end diastole thickness (LVPWd mm)
+ Left ventricular posterior wall end systole thickness (LVPWs mm)
+ Left Ventricular Mass (LVM - g)
- Left ventricular systolic function indexes:
+ End Diastolic Volume (EDV - ml)
+ End Systolic Volume (ESV - ml)
+ Cardiac output (CO - l/ph)
+ Fraction Shortening (FS%)
+ Ejection Fraction (EF%)
- Left ventricular diastolic function indexes:
+ Transmitral early diastolic peak velocity (E - cm/s).
+ Transmitral late diastolic peak velocity (A - cm/s).
+ E/A ratio
+ Deceleration Time (DT - ms)
+ Isovolumetric relaxation time (IVRT - ms)
+ Left ventricular Tei index
- Tissue Doppler Imaging at interventricular septum and lateral
mitral annulus:
+ Peak systolic velocity (Sm - cm/s)
+ Peak early diastolic velocity (Em - cm/s)
+ Peak late diastolic velocity (Am - cm/s)
+ E/Em ratio


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+ Em/Am ratio
2.2.6. Research ethics
- The subjects are fully explained and willing to participate in the
research. The implementation process is strictly complied with the
regulation of the Ministry of Health.
2.3. Data processing
- The collected data were processed according to the medical
statistics using Excel Plus and SPSS 20.0 statistical software.
2.6. Diagram of the study
Sửa lại:
Patient rheumatoid arthritis  Rheumatoid arthritis patients
Doppler ultrasound of cardiac muscle  Tissue Doppler Imaging
Describe…  Describe clinical and subclinical characteristics,
serum CRP level, serum TNF α level, some cardiac morphologic and
functional parameters in RA patients.
Understanding…  Understand the relationship between clinical,
subclinical characteristics, serum CRP level, serum TNF α level,
level of disease activity with some cardiac morphologic and
functional parameters in RA patients.

Fig 2.1. Study diagram


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CHAPTER 3: RESULTS
3.1. Clinical, subclinical characteristics, serum CRP
level, serum TNF-α level and some cardiac morphologic
and functional parameters in patients with rheumatoid
arthritis.
3.1.1. Clinical characteristics of patients with rheumatoid arthritis
Table 3.1. Some general characteristics of the study subjects
Characteristics

Rheumatoid arthritis Control group
(n = 122)
(n = 51)

p

Age (years)
48.9 ± 11,3
48.1 ± 11.7 > 0.05
Male, n (%)
19 (15.6%)
8 (15.7%)
> 0.05
Sex
Female, n (%)
103 (84.4%)
43 (84.3%) > 0.05
Height (cm)
155.99 ± 5.78
158.09 ± 6.47 < 0.05
Weight (kg)
51.23 ± 7.28
54.80 ± 7.52 < 0.05
BMI (kg/m²)
21.00 ± 2.65
21.87 ± 2.15 < 0.05
BSA (m²)
1.48 ± 0.12
1.54 ± 0.13 < 0.05
Systolic blood
119.30 ± 5.73
117.55 ± 8.27 > 0.05
pressure (mmHg)
Diastolic blood
77.21 ± 4.55
76.57 ± 4.74 > 0.05
pressure (mmHg)
Table 3.1 and 3.2. The most common age of RA patients was from
40 to 59 years old, accounting for 55.7%. 67.2% of patients with RA
had normal BMI.
Table 3.2. Some clinical features of rheumatoid arthritis patients
Rheumatoid arthritis (n = 122)
Clinical features
Median
Min-Max
X ± SD
Duration of RA
5.37 ± 5.25
3.60
0.3 – 25.0
Duration of Morning
61.48 ± 27.64
60
10 - 180
stiffness
The number of tender
13.30 ± 4.34
13
4 - 23
joints
The
number
of
9.95 ± 3.71
10
1 - 19
swollen joints
VAS score
67.38 ± 11.49
70
30 - 90
CDAI index
36.72 ± 9.08
37.00
11 - 60
SDAI index
39.28 ± 11.03
40.50
11.02 – 72.64
DAS28 CRP
5.77 ± 0.94
6.02
2.85 – 7.86


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DAS28 ESR
6.35 ± 0.89
6.54
3.50 – 8.11
Table 3.3. Duration of disease from 1 to 5 years accounted for 48.4%,
over 5 years represented 35.2%. Duration of morning stiffness from 45 to
60 minutes and over 60 minutes accounted for 45.9% and 34.4%,
respectively. Patients with severe pain (VAS score 70 – 100) made up
61.2%.
Table 3.3. Regarding DAS28 CRP, there were 74.6% of patients
with high disease activity and 23.8% of patients with moderate
disease activity.
3.1.2. Sub-Clinical characteristics of patients with rheumatoid arthritis
Table 3.4. and 3.5. Median ESR 1 hr and 2 hrs were high. There
were 25.4% of patients with anemia including 16.4% of patients with
mild anemia and 9.0% of patients with moderate anemia.
Table 3.6. RF concentration was 85.73 ± 73.74. High positive rate
was 63.1%.
3.1.3. Concentration of plasma CRP level, serum TNF-α
level of study subjects
Table 3.7. Characteristics of plasma CRP level, serum TNF-α level
Rheumatoid arthritis
Control group
p
Index
(n = 122)
(n = 51)
2.56 ± 2.81
0.12 ± 0.12
< 0.01
Plasma CRP level 1.77 (0.02 – 14.64)
0.08 (0.01 – 0.50)
(mg/dL)
Serum TNF-α,
15.32 ± 7.37
8.84 ± 2.17
< 0.01
level (pg/mL)
13.70 (6.22 – 38.50) 9.18 (4.51 – 12.90)
Plasma CRP level and serum TNFα level of RA patients were
higher than that of control group, p<0.01.
Table 3.8. Plasma CRP level was positively correlated to: the
number of tender joints, the number of swollen joints, duration of
morning stiffness, ESR 1h, DAS28 CRP, DAS28 ESR with r: 0.416;
0.475, 0.634, 0.632, 0.82, 0.72 with p < 0.001. There was no
correlation between plasma CRP level and serum TNF-α level at r =
0.133 and p > 0.05.


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Table 3.9. There was no difference between median TNF-α serum
concentration in patients with DAS28 CRP> 5.1 and that of patients
with DAS28 CRP ≤ 5.1 (p> 0.05).
Table 3.10. Serum TNF-α level was not correlated with: the
number of tender joints, the number of swollen joints, duration of
morning stiffness, plasma CRP level, ESR 1hr, DAS28 CRP, DAS28
ESR, p > 0.05.
3.1.4. Some cardiac morphologic and functional parameters study
subjects
Table 3.11. Some indexes of left ventricular morphology and
systolic function of RA patients and control group were similar, p >
0.05. IVSd, IVSs and LVPWs of RA patients were higher than that of
control group, p < 0.05.
Table 3.12. Wave A in RA patients was higher than that of the
control group, p < 0.01. There was no difference between Tei index
of RA patients and of control group, p > 0.05. E/A ratio and IVRT of
RA patients were lower than that of the control group, p < 0.05.
Table 3.13. Tissue doppler imaging at the interventricular septum:
Em of RA patients was lower than that of the control group, p < 0.05.
Em/Am ratio in study group was lower than that of the control group,
p < 0.01. There was no difference in Sm, Am and E/Em ratio of study
subjects and controls, p > 0.05. Tissue Doppler Imaging at lateral
mitral annulus: Em and Em/Am ratio of RA patients were lower than
that of the control group, p < 0.05. There was no difference in Sm,
Am and E/Em ratio of study subjects and controls, p > 0.05.
Table 3.14. and 3.15. The rate of left ventricular diastolic
dysfunction in RA patients was 35.2% which was higher than that of
the control group, at 17.7% (p < 0.01). Among 35.2% of patients with
rheumatoid arthritis who had left ventricular diastolic dysfunction,
the proportion of patients with left ventricular diastolic dysfunction
grade I, II, III were 16.4%, 18.0, and 0.8%, respectively.
3.2. The relationship between clinical, subclinical characteristics,
plasma CRP level, serum TNF-α level, level of disease activity
with some cardiac morphologic and functional parameters in RA
patients
3.2.1. The association between clinical, subclinical characteristics,
plasma CRP level, serum TNF-α level, level of disease activity with
some left ventricular morphologic indexes


13
Table 3.16. IVSd, IVSs and LVPWd values were positively correlated
to age and duration of disease. EF and FS indexes were in inverse
proportion to DAS28 CRP.
Table 3.17. IVSd, IVSs, LVPWd, LVPWs and LVM were positively
correlated to RF level. EF and FS indexes were negatively correlated to
plasma CRP levels. IVSs and LVPWd were positively correlated to
serum TNF-α level.
3.2.2. The relationship between clinical features with cardiac
function indexes
* The relationship between cardiac function indexes and age
Table 3.18. A wave of patient < 60 years old was lower than A
wave of patients ≥ 60 years old, p < 0.05. E/A ratio in patients < 60
years was higher than that of patients≥ 60 years old, p < 0.05. There
was no difference in left ventricular Tei index in < 60 years and
patients ≥ 60 years old, p > 0.05.
Figure 3.4. and 3.5. There was positive correlation between A wave,
IVRT and left ventricular Tei score, meanwhile, E / A ratio was negatively
correlated to the age of RA patients, p < 0.01.
Table 3.19. Tissue doppler imaging at the interventricular septum
and lateral mitral annulus: Em and Em/Am ratio of patients < 60
years were higher than that of patients ≥ 60 years, p < 0.05. Am index
of patients < 60 years was lower than that of patients≥60 years, p <
0.01.
Figures 3.6, 3.7, 3.8, and 3.9: Tissue doppler imaging at the
interventricular septum and lateral mitral annulus: there was negative
correlation between of Em index and E/Em ration, meanwhile Am
index and E/Em ratio were positively correlated to patient age, p <
0.01.
* The association between cardiac function indexes and duration of
disease
Table 3.20. There was no difference between E wave and A wave
in patients with disease duration ≤ 1 year and those with disease
duration> 1 year, p> 0.05.
Figures 3.10 and 3.11: E wave was negatively correlated E/A
ratio; meanwhile, there was positive correlation between A wave,
IVRT and duration of disease, p < 0.05.
Table 3.21. Tissue doppler imaging at the interventricular septum
and mitral annulus: in RA patients, the longer duration of disease
was, the higher E/Em ratio was, meanwhile Sm, Em, and Em/Am


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ratio decreased, p < 0.01. Tissue doppler imaging at lateral mitral
annulus: Patients with RA had a longer duration of disease, Em index
and Em/Am ratio decreased, p < 0.01.

Figure 3.12. There was a correlation between the Sm and Em indexes
at the interventricular septum and mitral annulus with disease
duration, p < 0.001.
Figures 3.13 and 3.15. At the interventricular septum and lateral
mitral annulus E/Em ratio was positively correlated with duration of
disease, in contrast to Em/Am ratio which was negatively correlated
to disease duration, p < 0.001.
Figure 3.14. At lateral mitral annulus, there was negative between
Em index and duration of disease, p < 0.001. Meanwhile, Am index
was positively correlated to disease duration p < 0.001.
3.2.3. The association between subclinical features and some
cardiac function indexes:
Table 3.22. E/A ratio was negatively correlated to RF concentration, p
< 0.05.
Table 3.23: There was negative correlation between Em at
interventricular septum and mitral annulus and RF concentration.
E/Em ratio at lateral mitral annulus was negatively correlated to Hb
concentration.
3.2.4. The relationship between plasma CRP level, serum TNFα
level and cardiac indexes


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Table 3.24. There was positive correlation between plasma CRP level
and left ventricular Tei index, r = 0.283; p < 0.05.
Table 3.25. There was no relation between plasma
CRP concentration and Tissue Doppler Imaging indexes
at interventricular septum and mitral annulus, p> 0.05.
Figure 3.16. There was positive correlation between plasma CRP
level and Am index at lateral mitral annulus, p < 0.05.
Table 3.26. and 3.27. There was positive correlation between serum
TNF-α level and DT, and E/Em ratio at interventricular septum
and mitral annulus. There was negative correlation between Em,
Em/Am interventricular septum and mitral annulus, and E/Em
at lateral mitral annulus, p < 0.05.
Figure 3.17. and 3.18. There was negative correlation between Em
index, Em/Am ratio at interventricular septum and mitral
annulus, Em at lateral mitral annulus. E/Em ratio at lateral mitral annulus
was negatively correlated to serum TNF-α level, p < 0. 05.
3.2.5. The relationship between level of disease activity and cardiac
function indexes
Table 3.28. Mitral valve Tissue doppler imaging: there was no
difference between E wave and E/A ratio of RA patients with DAS28
CRP > 5.1 and that of those with DAS28 CRP ≤ 5.1, p > 0.05.
Table 3.29. Tissue doppler imaging at the interventricular septum
and lateral mitral annulus: there was no difference between Em,
E/Em, and Em/Am in RA patients with DAS28 CRP > 5.1 and that of
RA patients with DAS28 CRP ≤ 5.1, p > 0.05.
Tables 3.30 and 3.31. DAS28 CRP index was not correlated with
mitral valve Doppler echocardiography indexes, left ventricular Tei
index and Tissue doppler imaging at the interventricular septum and
lateral mitral annulus indexes, p > 0.05.


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Table 3.32. The relationship between left ventricular diastolic
dysfunction and DAS28 CRP
Index Diastolic function
No diastolic
Total
(n = 43)
dysfunction
n
DAS28
(n = 79)
CRP
≤ 5.1
11
20
31
> 5.1
32
59
91
Total
43
79
122
OR = 0.986 (CI 95%: 0.421 – 2.313); χ²; 0.001; p = 0.974
There was no difference in risk of left ventricular diastolic
dysfunction between patients with DAS28 CRP > 5.1 and those with
DAS28 ≤ 5.1, OR = 0.986 (CI 95%: 0.421 - 2.313), p = 0.974 .

CHAPTER 4: DISCUSSION
4.1. Clinical, subclinical characteristics, plasma CRP level, serum
TNF-α level and some cardiac morphologic and functional
parameters in patients with rheumatoid arthritis.
4.1.1. Clinical characteristics of patients with rheumatoid arthritis
Age, gender, systolic blood pressure, diastolic blood pressure of
study subjects were similar to that of controls, p > 0.05. Height,
weight, BMI, BSA of study subjects were lower than the data of
controls, p < 0.05.
Duration of disease was 5.37 ± 5.25 years. Duration of morning
stiffness was 61.48 ± 27.64 (minutes).
The number of swollen joints was 9.95 ± 3.71, the number of
tender joints was 13.30 ± 4.34. VAS score was 67.38 ± 11.49. DAS28
CRP was 5.77 ± 0.94.
4.1.2. Sub-Clinical characteristics of patients with rheumatoid
arthritis
Hb concentration was 129.44 ± 14.32 (g/L). 25.4% of RA patients
had anemia. Among anemic RA patients, the proportions of mild
anemia and moderate anemia were 16.4% and 9%, respectively.


17
RF level was 85.73 ± 73.74 (IU/mL), the percentages of patients
with negative RF, low-positive RF, and high-positive RF were 24.6%,
12.3%, 63.1%, respectively.
4.1.3. Concentration of plasma CRP levels, serum TNF-α
levels of study subjects
Plasma CRP level of patients was 2.56 ± 2.81 (mg/dL) which was
higher than that of controls, 0.12 ± 0.12 (mg/dL) (p <0.01). Plasma
CRP level was positively correlated to the number of tender joints,
the number of swollen joints, duration of morning stiffness, ESR 1hr
and DAS28 CRP, DAS28 ESR, p < 0.001. There was no correlation
between plasma CRP level and serum TNF-α level.
According to Shrivastava A.K. et al. (2015), Yildirim K. et al
(2004) and Nguyen Huy Thong (2017), our results are consistent with
these previous research.
4.1.3.2. Serum TNF-α level
Serum TNF-α level of RA patients was 15.32 ± 7.37 (pg/mL)
(6.22-3.8.50, median 13.70) which was higher than that of controls,
8.84 ± 2.17 (pg/mL) (4.51-12.90, median 9.18) (p < 0.001).
According to Hanan M. et al. (2015), Shrivastava A.K. et al.
(2015), Tomas L. et al. (2013) and Ebrahimi A.A. et al. (2009) our
results are consistent with these previous research.
There was no difference between RA patients with
DAS28 CRP > 5.1, serum TNF-α of 16.02 ± 7.50
(pg/mL), median of 14.10 and those who had DAS28
CRP ≤ 5.1, serum TNF-α level 13.26 ± 6.64 (pg/mL),
median of 11.30 (p > 0.05). Our results are consistent
with findings of Beyazal M.S. et al. (2017).
Serum TNF-α level was not correlated to the number of tender joints,
the number of swollen joints, duration of morning stiffness, plasma CRP
concentration, ESR 1hr, DAS28 CRP and DAS28 ESR.
4.1.4. Some cardiac morphologic and functional parameters study
subjects
4.1.4.1. Some left ventricular morphologic indexes and systolic function of
study subjects
Dd, Ds, LVPWd, and LVM of study subjects were similar to that
of controls, p > 0.05. IVSd, IVSs and LVPWs of RA patients in this
study were higher than that of controls, p < 0.05. There was a


18
similarity between EF%, FS%, EDV, ESV, CO of study subjects and
of controls, p > 0.05.
Our results are consistent with findings of Muizz A.M. et al.
(2011), Udayakumar N. et al. (2007), Rexhepaj N. et al. (2006).
4.1.4.2. Some cardiac function indexes of study subjects
RA patients had significant left ventricular diastolic dysfunction
that was illustrate by E/A ratio. E/A ratio of RA patients was 1.02 ±
0.35 which was lower than that of controls, 1.11 ± 0.28 (p < 0.05). A
wave of study subjects was 71.44 ± 15.84 (cm/s) which was higher
than A wave of controls, 64.82 ± 12.41 (cm/s) (p < 0.01). Our results
are consistent with findings of Fatma, E. et al. (2015).
DT index of patients was 162.93 ± 49.79 (ms) which was lower
than DT index of controls, 184.49 ± 37.51 (ms) (p <0.01). IVRT of
patients was 78.34 ± 23.16 (ms) which was lower than that of
controls, 84.31 ± 16.27 (ms) (p < 0.05).
There was no difference between Tei index of study subjects (0.61
± 0.35) and that of controls (0.55 ± 0.09), p > 0.05.
Tissue doppler imaging at the interventricular septum and mitral
annulus: There was no difference between Sm wave of subjects (8.26
± 1.56 (cm/s)) and of controls (8.09 ± 1.22 (cm/s)), p> 0. 05. E wave
of patients was 9.44 ± 2.91 (cm/s) which was lower than that of
controls (10.23 ± 2.42 (cm/s)), p <0.05. There was no difference
between Am wave of study subjects (10.18 ± 2.64 (cm / s)) and
controls (9.36 ± 2.23 (cm/s)) p> 0.05. There was no difference
between E/Em of study research (7.82 ± 2.03) and controls 7.03 ±
1.43 with p > 0.05. Em/Am ratio of RA patients was 1.01 ± 0.48
which was lower than that of controls (1.17 ± 0.45), p < 0.01.
Our results are consistent with findings of Fatma E. et al. (2012),
Wislowska M. et al. (2008), Birdane A. et al. (2007) and Arslam S. et
al. (2006).
Tissue doppler imaging at lateral mitral annulus: there was no
difference between Sm wave of study subjects which was 9.83 ± 2.49
(cm / s) and that of controls (9.20 ± 2.27 (cm / s)), p> 0.05. E wave of
RA patients was 12.77 ± 3.98 (cm / s) which was lower than that of
controls, 13.94 ± 3.69 (cm / s), p < 0.05. There was no difference
between Am wave of patients, which was 10.83 ± 2.84 (cm / s), and
Am wave of controls, 10.23 ± 2.64 (cm / s), p > 0.05. E/Em ratio of


19
patients was 5.85 ± 2.09 which did not differ from from that of
controls, 5.02 ± 1.39 (p > 0.05). Em/Am ratio of subjects was 1.29 ±
0.61 which was lower than that of controls, 1.48 ± 0.57 (p < 0.05).
Our results are consistent with findings of Sitia S. et al. (2012) and
Birdane A. et al. (2007).
* The rate of left ventricular diastolic dysfunction
35.2% of patients with RA had left ventricular diastolic
dysfunction which was higher than the proportion of people who had
left ventricular diastolic dysfunction in the control group, 17.7% (p <
0.05). There percentages of patients with grade I, II, and III left
ventricular diastolic dysfunction were 16.4%, 18.0%, and 0.8%,
respectively.
Our results are consistent with findings of Liang K.P. et al. (2010),
Fatma E. et al. (2015), Gonzalez-Juanatey C. et al. (2004).
4.2. The relationship between clinical, subclinical characteristics,
plasma CRP level, serum TNF-α level, level of disease activity
level and some cardiac morphologic and functional parameters in
patients with RA.
4.2.1. The relationship between clinical, subclinical characteristics,
plasma CRP level, serum TNF-α level, level of disease activity level
and some morphologic indexes of left ventricle
IVSd (r = 0.39, r = 0.39, p <0.01), IVSs (r = 0.41; r = 0.28; p
<0.01) and LVPWd (r = 0.40; r = 0.28; p < 0.01) were positively
correlated to with age and duration of disease. There were negative
correlations between EF (r = 0.24; p < 0.01) and DAS28 CRP. FS (r
= 0.27; p < 0.01) was negatively correlated to DAS28 CRP.
There were positive correlation between RF concentration and the
following indexes: IVSd (r = 0.21; p < 0.01), IVSs (r = 0.25; p <
0.01), LVPWd (r = 0.26; p < 0.01), LVPWs r = 0.25; p < 0.01) and
LVM (r = 0.257; p < 0.01). CRP level was negatively correlated to
EF (r = 0.23, p < 0.01) and FS (r = 0.29; p <0.01). Serum TNF-α
level was positively correlated to IVSs (r = 0.20, p < 0.01) and
LVPWd (r = 0.19; p <0.01). Our results are consistent with findings
of to Wislowska M. et al. (2008) and Muizz A.M. et al. (2011).
4.2.2. The association between clinical features and some cardiac
function indexes


20
4.2.2.1. The relationship between some cardiac function indexes and
age
There were positive correlations between some Tissue Doppler
echocardiogram indexes including A wave (r = 0.392, p <0.01), IVRT
= 0.351; p <0.01), left ventricular Tei index (r = 0.225; p < 0.01) and
age in RA patients. E/A ratio (r = -0.356; p<0.01) was negatively
correlated to age.
Tissue doppler imaging at interventricular spetum and mitral
annulus in RA patients: Am index (r = 0.425, p < 0.01), rate E/Em (r
= 0.242; p < 0.01) were positively correlated to age, meanwhile Em
index (r = - 0.461; p < 0.01) and Em / Am ratio (r = - 0.555; p < 0.01)
were negatively correlated to age.
Tissue doppler imaging at lateral mitral annulus in RA patients:
Am (r = 0.497; p < 0.001) and E/Em ratio (r = 0.357; p < 0.001) were
positively correlated to age, in contrast to Em (r = - 0.580; p < 0.001),
Em/Am ratio (r = - 0.676; p < 0.01) that were negatively correlated to
age.
Our results are consistent with findings of Muizz A.M. et al. (2011),
Wislowska M. et al. (2008), Birdane A. et al. (2007).
4.2.1.2. The association between some cardiac function indexes and
duration of disease
Mitral valve Tissue doppler imaging: A wave (r = 0.191, p < 0.05)
and IVRT (r = 0.231, p < 0.05) were positively correlated to duration of
disease, meanwhile E wave (r = - 0.266; p < 0.01) and E/A ratio (r = - 0.260;
p < 0.01) were negatively correlated to duration of disease.
Our results are consistent with finding of Wislowska M. et al.
(2008), Rexhepaj N. et al. (2006), Arslam S. et al. (2006) and
Udayakumar N. et al. (2007).
Tissue doppler imaging at interventicular spetum and mitral
annulus: Sm (r = - 0.270; p < 0.01), Em (r = - 0.717; p < 0.001),
Em/Am ratio (r = - 0.482; p < 0.001) were negatively correlated to
duration of disease, there was positive correlation between E/Em ratio (r
= 0.520; p < 0.001) and duration of disease.
Tissue doppler imaging at lateral mitral annulus in RA patients:
Am (r = 0.318; p < 0.001) and E/Em ratio (r = 0.311; p < 0.001) were
positively correlated to duration of disease, meanwhile Em (r = - 0.594;


21
p < 0.001) and Em/Am (r = - 0.498; p < 0.001) were negatively
correlated to duration of disease.
Our results are consistent with findings of Arslam S. et al. (2006),
Birdane A. et al. (2007), Davis J.M. et al. (2015) and Liang K.P. et al.
(2010).
The association between duration of the disease and left
ventricular diastolic dysfunction indicates the effect of chronic
autoimmune inflammation on cardiac function in RA. There is a
relation between some left ventricular diastolic function indexes and
duration of disease.
4.2.3. The association between subclinical characteristics and some
cardiac function indexes
There was negative correlation between E/Em ratio (r = - 0.23)
(Tissue Doppler Imaging at lateral mitral annulus) and Hb
concentration, p < 0.05. According to Maradit-Kremers, H. et al.
(2007), inflammation and anemia are related to the onset of diastolic
dysfunction.
Tissue Doppler Imaging at interventricular septum and mitral
annulus: E/A ratio (r = - 0.18) and Em (r = - 0.20) were negatively
correlated to RF concentration, p < 0.05. According to Liang K.P. et
al. (2009), positive RF was statistically significant associated with
risk of heart failure (OR: 3.1; CI 95% 0.8 - 12).
Thus, anemia and RF concentration may be risk factors of heart
failure in patients with RA. This result is consistent with findings
published by some other authors.
4.2.4. The relationship between plasma CRP level and serum TNFα level with some cardiac function indexes
Plasma CRP level was positively correlated to left ventricular Tei
index (r = 0.283; p <0.05) and Am index (TDI at lateral mitral
annulus) (r = 0.222; p < 0.05). Our results are consistent with Muizz
A.M. et al. (2011), Liang K.P. et al. (2010).
Serum TNF-α level was positively correlated to DT (r = 0.215, p <
0.05) and E/Em at lateral mitral annulus (r = 0.183, p < 0.05),
meanwhile it was negatively correlated to Em at interventricular
septum and mitral annulus (r = - 0.218; p < 0.05), Em/Am ratio at at
interventricular septum and mitral annulus (r = - 0.204; p < 0.05), and
Em at lateral mitral annulus (r = - 0.185; p < 0.05). Our results are


22
consistent with findings of Tomas L. et al. (2013), Liang K.P. (2010)
that indicates the role chronic autoimmune inflammation in the
development of diastolic dysfunction in patients with rheumatoid
arthritis.
4.2.5. The association between level of disease activity and some
cardiac function indexes
Mitral valve Doppler echocardiograph: There was no difference in
E wave of RA patients with DAS28 CRP > 5.1 and that of RA
patients with DAS28 CRP ≤ 5.1 (p > 0.05). Tissue Doppler imaging
at interventricular septum and lateral mitral annulus: There was no
difference in E wave, E/Em ratio, Em/Am ratio of RA patients with
DAS28 CRP > 5.1 and that of patients with DAS28 CRP ≤ 5.1 with p
> 0.05.
DAS28 CRP did not correlate with E wave, A wave, E/A ratio, DT
index, IVRT index and left ventricular Tei index (p > 0.05). DAS28
CRP did not correlate with Tissue Doppler Imaging indexes at
interventricular septum and lateral mitral annulus (p > 0.05).
There was no difference in risk of left ventricular diastolic
dysfunction between patients with DAS28 CRP > 5.1 and those who
had DAS28 CRP ≤ 5.1; OR = 0.986 (95% CI: 0.421 - 2.313); χ²;
0.001; p = 0.974. This result is consistent with findings of other
authors such as Wislowska M. et al (2008), Birdane A. et al (2007),
Muizz A.M. et al (2011).

CONCLUSIONS
1. Clinical, subclinical characteristics, plasma CRP level,
serum TNF-α level, and some cardiac morphologic and
functional parameters in RA patients.
- The mean age was 48.9 ± 11.3 years, female/male ratio was 5/1,
the average duration of disease was 5.37 ± 5.25 years, the mean
duration of morning stiffness was 61.48 ± 27.64 minutes, the average
number of tender joints was 13.30 ± 4.34 joints, the average number
of swollen joints was 9.95 ± 3.71 joints. There were 74.6% of
patients with high disease activity.


23
- There were 25.4% of patients with anemia. The proportions of mild
anemia and moderate anemia were 16.4%, and 9%, respectively. There
were 75.4% of patients with positive RF.
- Plasma CRP concentration of RA patients was higher than that of
controls (2.56 ± 2.81 vs. 0.12 ± 0.12 mg/dL, p < 0.001). It was positively
correlated to: the number of swollen joints, the number of tender joints,
ESR 1hr, DAS28 CRP and DAS28 ESR (p < 0.001). There was no
correlation between plasma CRP level and serum TNF-α level.
- Serum TNF-α level of RA patients was higher than that of
controls (15.32 ± 7.37 vs. 8.84 ± 2.17 pg / mL; p <0.001). It was not
correlated to the number of swollen joints, the number of tender
joints, ESR 1hr, DAS28 CRP and DAS28 ESR.
- There was no difference between some left ventricular
morphologic and systolic function indexes of RA patients and that of
control group.
- There were some changes in cardiac function indexes in patients
with rheumatoid arthritis compared with the control group:
+ Mitral valve Pulsed Doppler Echocardiography: A wave of RA
patients was higher than that of controls, p < 0.01. E/A ratio, DT,
IVRT of PA patients were lower than that of controls, p < 0.05.
+ Tissue Doppler Imaging at interventricular septum and lateral
mitral annulus: Em and Em/Am of RA patients were lower than that
of controls, p < 0.05.
- The percentage of RA patients with left ventricular diastolic
dysfunction was 35.2% which was higher than that of controls,
17.7% (p < 0.01). In RA patients, the proportion of grade I, II, III
dysfunction were 16.4%, 18%, and 0.8%, respectively.
2. The relationship between clinical, subclinical characteristics,
plasma CRP level, serum TNF-α level, level of disease activity and
some cardiac morphologic and functional parameters in patients with
rheumatoid arthritis.
- In RA patients, IVSd and LVPWd index were positively correlated
to age (r = 0.39, r = 0.40), duration of disease (r = 0.39, r = 0.28), RF
concentration (r = 0.21; r = 0.26); p < 0.01.
- In PA patients, Em (r = - 0.461), Em/Am ratio (r = - 0.555) at
interventricular septum and mitral annulus, Em (r = - 0.580), Em/Am


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